CD147 and Corneal Wound Repair

描述（由申请人提供）：角膜损伤后的愈合过程是通过释放一些蛋白质来启动的，这些蛋白质会分解上皮连接并促进上皮片的运动以覆盖受伤区域。基质金属蛋白酶（MMPs）是降解细胞表面和细胞外基质成分的蛋白水解酶家族，在这一过程中起着核心作用。在未受伤的角膜中很少检测到，它们的诱导被认为在伤口愈合和慢性伤口的建立中起关键作用。MMPs的产生和激活受到复杂机制的严格调控，包括CD147的同质寡聚化，CD147是一种在肿瘤细胞中高度表达的高度n -糖基化的跨膜蛋白。我们最近发现CD147是一种新的半乳糖凝集素-3的细胞表面对抗受体，半乳糖凝集素-3是一种已知具有聚集性的半乳糖苷结合凝集素

DESCRIPTION (provided by applicant): The healing process after corneal injury is initiated through the release of a number of proteins that disassemble the epithelial junctions and contribute to the movement of the epithelial sheet to cover the wounded area. Matrix metalloproteinases (MMPs), a family of proteolytic enzymes that degrade components of the cell surface and extracellular matrix, are central to this process. Barely detected in unwounded cornea, their induction is thought to play a key role during wound healing and in the establishment of chronic wounds. The production and activation of MMPs are tightly regulated by complex mechanisms that include homo-oligomerization of CD147, a heavily N-glycosylated transmembrane protein highly expressed in tumor cells. We recently discovered that CD147 is a novel cell surface counter-receptor for galectin-3, a �alactoside-binding lectin known to cluster cell surface receptors. More importantly, we found that clustering of CD147 by galectin-3 dramatically upregulates MMP9, the primary metalloproteinase synthesized and secreted by corneal epithelial cells migrating to resurface a wound. The long-term objective of this proposal is to determine whether induction of CD147 clustering by galectin-3 is a powerful regulatory mechanism of the physiological and pathological remodeling processes associated with wound repair in the cornea. The following specific aims will address this objective: (1) to investigate te role of CD147 clustering by galectin-3 as modulator of collective cell detachment and cell migration in corneal epithelial cells, and to determine whether degradation of the galectin-3 by MMP9 inhibits CD147 clustering, thereby constituting a negative feedback mechanism to prevent sustained corneal remodeling, (2) to investigate the role of CD147 N-glycosylation in modulating galectin-3 binding affinity, CD147 clustering, and MMP9 induction, and (3) to characterize the biological role of the CD147/galectin-3 complex in mouse models of wound healing and recurrent erosion, and determine whether inhibiting galectin-3 receptor clustering and CD147 function have a therapeutic potential during recurrent epithelial wound healing. This research will explore, for the first time, the molecular mechanism linking glycan dynamics to the biological process by which wounded tissue initiates epithelial cell detachment and migration, and will provide better insight into the pathogenesis of chronic wounds.